Sex Differences in Circulating Progenitor Cells

Lower levels of circulating progenitor cells (PCs) reflect impaired endogenous regenerative capacity and are associated with aging, vascular disease, and poor outcomes. Whether biologic sex and sex hormones influence PC numbers remains a subject of controversy. We sought to determine sex differences in circulating PCs in both healthy persons and patients with coronary artery disease, and to determine their association with sex hormone levels.

In 642 participants (mean age 48 years, 69% women, 23% black) free from cardiovascular disease, we measured circulating PC counts as CD45^med+ mononuclear cells coexpressing CD34 and its subsets expressing CD133, chemokine (C-X-C motif) receptor 4, and vascular endothelial growth factor receptor 2 epitopes using flow cytometry. Testosterone and estradiol levels were measured. After adjustment for age, cardiovascular risk factors, and body mass, CD34⁺ (β=-23%, P<0.001), CD34⁺/CD133⁺ (β=-20%, P=0.001), CD34⁺/chemokine (C-X-C motif) receptor 4-positive (β=-24%, P<0.001), and CD34⁺/chemokine (C-X-C motif) receptor 4-positive/CD133⁺ (β=-21%, P=0.001) PC counts, but not vascular endothelial growth factor receptor 2-positive PC counts were lower in women compared with men. Estradiol levels positively correlated with hematopoietic, but not vascular endothelial growth factor receptor 2- positive PC counts in women (P<0.05). Testosterone levels and PC counts were not correlated in men. These findings were replicated in an independent cohort with prevalent coronary artery disease.

Women have lower circulating hematopoietic PC levels compared with men. Estrogen levels are modestly associated with PC levels in women. Since PCs are reflective of endogenous regenerative capacity, these findings may at least partly explain the rise in adverse cardiovascular events in women with aging and menopause.